Clinically relevant subgroups in COPDand asthma

Alice M. Turner1,2, Lilla Tamasi3, Florence Schleich4, Mehmet Hoxha5,Ildiko Horvath3, Renaud Louis4 and Neil Barnes6

Affiliations: 1Clinical and Experimental Medicine, University of Birmingham, Queen Elizabeth HospitalBirmingham, Birmingham, UK. 2Dept of Respiratory Medicine, Birmingham Heartlands Hospital, Birmingham,UK. 3Dept of Pulmonology, Semmelweis University, Budapest, Hungary. 4Respiratory Medicine, CHU Sart-Tilman B35, Liege, Belgium. 5Service of Allergology and Clinical Immunology, UHC “Mother Teresa”, Tirana,Albania. 6GlaxoSmithKline, Stockley Park West, Uxbridge, UK.

Correspondence: Alice M. Turner, Clinical and Experimental Medicine, University of Birmingham, QueenElizabeth Hospital Birmingham, Mindelsohn Way, Birmingham, B15 2WB, UK. E-mail: a.m.wood@bham.ac.uk

ABSTRACT As knowledge of airways disease has grown, it has become apparent that neither chronicobstructive pulmonary disease (COPD) nor asthma is a simple, easily defined disease. In the past,treatment options for both diseases were limited; thus, there was less need to define subgroups. Astreatment options have grown, so has our need to predict who will respond to new drugs. To date,identifying subgroups has been largely reported by detailed clinical characterisation or differences inpathobiology. These subgroups are commonly called “phenotypes”; however, the problem of defining whatconstitutes a phenotype, whether this should include comorbid diseases and how to handle changes overtime has led to the term being used loosely.

In this review, we describe subgroups of COPD and asthma patients whose clinical characteristics webelieve have therapeutic or major prognostic implications specific to the lung, and whether thesesubgroups are constant over time. Finally, we will discuss whether the subgroups we describe are commonto both asthma and COPD, and give some examples of how treatment might be tailored in patients wherethe subgroup is clear, but the label of asthma or COPD is not.

@ERSpublicationsSummary of subgroups of airways disease that can be found in COPD and asthma, and theirmanagement http:///ow.ly/KiDvo

IntroductionAs knowledge of airways disease has grown, it has become apparent that neither chronic obstructivepulmonary disease (COPD) nor asthma is an easily defined disease. Various new definitions have beenproposed [1–3], largely focusing on identifying subgroups by detailed clinical characterisation ordifferences in pathobiology. These subgroups are commonly called “phenotypes” and in some casescorrespond with the Oxford English Dictionary definition of a phenotype: “The sum total of theobservable characteristics of an individual, regarded as the consequence of the interaction of theindividual’s genotype with the environment”. This definition does not include treatment or prognosis, buthas strengths in that it helps us to observe clusters of characteristics and delineate new phenotypes where,

Copyright ©ERS 2015. ERR articles are open access and distributed under the terms of the Creative CommonsAttribution Non-Commercial Licence 4.0.

Received: July 21 2014 | Accepted after revision: Sept 22 2014

Support statement: This study was not supported by any specific funding, although the authors met and began theprocess of researching the review at an educational event sponsored by GSK. L. Tamasi has received funding from theHungarian Respiratory Society. F. Schleich and R. Louis have been supported by the Interuniversity Attraction Poles(IAP) Project, Brussels, Belgium (P6/35 and P7/30).

Conflict of interest: Disclosures can be found alongside the online version of this article at err.ersjournals.com

Provenance: Submitted article, peer reviewed.

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many years later, further research can lead to treatment. However, the utility of some phenotypes inclinical practice remains uncertain due to inconsistency of definition, accumulation of comorbid diseases,the propensity of both asthma and COPD to change over time, and the lack of a clear relationship withdefined treatment strategies.

In this review we describe a series of clinically relevant subgroups in COPD and asthma, i.e. patients withclearly defined clinical characteristics (phenotype) and whom we believe have prognostic or therapeuticimplications specific to the lung. Using this definition, commonly associated comorbidities would not bepart of the way the subgroup was defined unless the cluster of comorbidities were specific to COPD orasthma, or altered pulmonary management. Behavioural characteristics, such as poor compliance withtreatment, would also fall outside our subgroups as they affect many diseases equally. We will also reviewthe evidence for the stability of these subgroups over time, the degree to which they overlap betweenCOPD and asthma, and what this implies for therapy.

Clinically relevant subgroups in COPDCOPD is an umbrella term covering many underlying processes that may lead to fixed airflow obstruction.Several large clinical trials and cohort studies have begun to delineate COPD subgroups where there is aclear treatment implication (table 1). A number of other subgroups, where the picture regarding treatmentis not as clear or which are more clinically relevant because of their implication for prognosis thantreatment, are shown in figure 1.

Comorbidity in COPD influences prognosis [29] and health-related quality of life (HRQoL) [30] andshares aspects of pathogenesis [31]. However, there remains considerable debate as to whether comorbiddisease represents a specific subgroup. Common comorbidities in COPD include osteoporosis, ischaemicheart disease, anxiety and depression. Most common comorbidities impair outcome in COPD patients,have clear treatment implications if present, and are treated similarly whether the patient has COPD ornot (table 2). These treatments are not specific to the underlying airway disease and, thus, do not formpart of our definition of a clinically relevant subgroup.

TABLE 1 Subgroups of chronic obstructive pulmonary disease (COPD) that currently havespecific treatments

Subgroup Treatment Effect of treatment [Ref.]

Frequent exacerbator LABA, LAMA, LABA/ICS,roflumilast, macrolides

Reduced exacerbations,better HRQoL,

improved lung function,possible effect on FEV1decline¶ and mortality¶

[4–11]

Chronic bronchitis Roflumilast, mucolytics Reduced exacerbations,improved HRQoL

[12–14]

α1-antitrypsin deficiency α1-antitrypsin augmentation Reduced progressionof emphysema

[15]

Upper zone dominantemphysema andbullous emphysema

LVRS Improved lung function,reduced exacerbations

[16, 17]

Type 1 respiratory failure LTOT Improved survivaland HRQoL

[18, 19]

Type 2 respiratory failure Domiciliary NIV Improved survival,possible effect onhospital admissions

and HRQoL

[20–24]

Eosinophilic COPD# Steroids Reduced exacerbations,improved lung function

[25–27]

Biomass COPD Removal of biomass exposure Reduced FEV1 decline [28]

Frequent exacerbator, chronic bronchitis and α1-antitrypsin deficiency are stable over time; the othersubgroups may vary according to disease severity or evidence is not yet clear. LABA: long-actingβ-agonists; LAMA long-acting muscarinic antagonists; ICS: inhaled corticosteroids; HRQoL; health-relatedquality of life; FEV1: forced expiratory volume in 1 s; LVRS: lung volume reduction surgery; LTOT:long-term oxygen therapy; NIV: noninvasive ventilation. #: see “Subgroups shared between COPD andasthma” section; ¶: effect only reported for LABA/ICS.

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The only possible exception to this is osteoporosis, which is almost twice as common in subjects withairflow obstruction compared to those without [48], is particularly associated with emphysema [40] andhas been shown to change with pulmonary treatment (e.g. lung volume reduction surgery (LVRS)). Aprospective cohort study [49] looking at the effect of LVRS on bone mineral density (BMD) in patientswith severe COPD concluded that surgery significantly improved BMD compared to pulmonaryrehabilitation. The increase correlated with residual volume, diffusing capacity of the lung for carbonmonoxide and fat-free mass, suggesting that restoration of respiratory dynamics, gas exchange andnutritional status induced an improvement in bone metabolism and mineral content independent ofexercise. However, changes in BMD could occur with increased activity resulting in the beneficial effect ofLVRS and may have confounded results. Furthermore, most interventional studies of osteoporosis outsideCOPD show more modest BMD improvement, generally in the range of 3–8% [41], whereas LVRSpatients in this study improved by up 24%, suggesting that the result should be interpreted with caution.The degree to which the relationship between osteoporosis and emphysema is confounded by prior steroidtreatment is not clear, but there are male patients with little or no steroid exposure who developosteoporosis, suggesting that it may not be entirely iatrogenic [50]. However, further studies are indicatedto understand mechanisms and determine optimal treatment.

Pulmonary

hypertension

Systemic

inflammation

Bronchiectasis

Bacterial

colonisation

Reduced

survival

Increased

exacerbation

frequency

FIGURE 1 Chronic obstructive pulmonary disease subgroups without clear treatment implications. The figure shows thesubgroups with clear prognostic implications for patients that are clinically relevant, but where therapeutic strategies areas yet unclear. The directions of the arrows indicate the probable direction of the association, e.g. patients with morefrequent exacerbations are less likely to survive. The direction of association of bacterial colonisation and bronchiectasisis not clear; thus, a bidirectional arrow is shown.

TABLE 2 Common comorbidities in chronic obstructive pulmonary disease (COPD)

Comorbidity Effect/associations ofcomorbidity in COPD

Treatment [Ref.]

Ischaemic heartdisease

Increased mortality β-blocker, ACE-I, aspirin,statin, nitrates

[32, 33]

Congestive cardiacfailure

Increased symptom burden,increased mortality

As above, plus diureticsDigoxin and implantable

devices may be used in somepatients

[32, 34]

Anxiety Poor HRQoL, increasedmortality, increased hospital

admissions

CBT, benzodiazepines,exercise

[35–37]

Depression Poor HRQoL, increasedmortality, increased hospital

admissions

CBT, anti-depressants,exercise

[37–39]

Osteoporosis Reduced physicalperformance, poor lung

function

Calcium supplements,bisphosphonates

[40–44]

GORD More frequent exacerbations PPI, H2 receptor antagonist [45–47]

This is not an exhaustive list of all conditions or treatments; where possible, references specific to COPD,major review articles or international guidelines on management have been cited rather than singlestudies. GORD: gastro-oesophageal reflux disease; ACE-I: angiotensin-converting enzyme inhibitor; HRQoL:health-related quality of life; CBT: cognitive behavioural therapy, PPI: proton-pump inhibitor.

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Subgroups with implications for treatmentFrequent exacerbators, defined as those with more than two exacerbations a year, were definitively describedin the ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points) study [51].Treatment options in this group include bronchodilators, long-acting β-agonists (LABA)/inhaledcorticosteroids (ICS), roflumilast and azithromycin. In a number of trials, bronchodilation has been shownto reduce exacerbation frequency. Long-acting muscarinic antagonists (LAMA) appear to exhibit this as aclass effect, e.g. tiotropium and glycopyrronium both reduced exacerbation frequency by >20% in theGLOW2 trial and were not statistically different in this regard [5]. A meta-analysis of LABAs showed areduction in exacerbations that was close to 20%, although differences between them were reported;formoterol only reduced exacerbations when used alongside ICS, whereas salmeterol had an effect when usedalone [6]. LAMA may be superior to LABA at reducing exacerbations, as shown in the POET (Prevention ofExacerbations of COPD) study (tiotropium versus salmeterol) [11]. LAMA/LABA also reduce exacerbationfrequency, although the effect does not appear additive. For example, in the SPARK study (indacaterol andglycopyrronium), the combination only reduced exacerbations by a further 12% over monotherapy [52].LABA/ICS have been demonstrated to improve lung function and HRQoL and to reduce exacerbations by∼25% in COPD patients [7]. Whilst most COPD trials have not focused on frequent exacerbators,international guidelines recognise the impact of certain drug classes on exacerbation frequency, emphasisingthe role of LABA/ICS [53]. Macrolides have become a hot topic throughout respiratory medicine, primarilybecause of their potential anti-inflammatory effects. In COPD, the largest study to date used azithromycinand prolonged time to first exacerbation from 174 to 266 days, implying it might be useful in frequentexacerbators [10]. Long-term safety issues include resistance and have been discussed elsewhere [54].

Chronic bronchitis occurs in 45% of COPD patients [55] and is linked to higher exacerbation frequencyand, hence, risk of decline [56]. Specific therapies for patients with chronic bronchitis have been reviewedelsewhere [57]. Roflumilast appears to prevent exacerbations best in COPD patients who have chronicbronchitis [14], although utility may not be restricted to this group. Its use provided modest butsignificantly improved forced expiratory volume in 1 s (FEV1) compared with placebo and a reduction inexacerbations. Mucolytics have also been used to reduce sputum viscosity and aid expectoration; thosemost widely used are carbocysteine and N-acetylcysteine. Whilst trials have not been specific to chronicbronchitis, their mechanism of action suggests they will work best in chronic sputum producers. The mostrecent systematic review of clinical effectiveness of mucolytics included 30 studies and demonstrated asmall, but statistically significant, reduction in exacerbations in treated COPD patients [12].

α1-antitrypsin deficiency (AATD) is the textbook case of a subgroup in COPD. It is associated with lowerzone dominant emphysema [58], although significant heterogeneity exists, possibly due to geneticmodifiers, as in usual COPD [59]. Augmentation therapy for AATD has been routinely used in somecountries since the first trials were completed; a meta-analysis has demonstrated that it may reduceemphysema progression [15]. Further trials, including inhaled α1-antitrypsin, are due to be published soonand other specific therapies may become available in due course [60].

Upper zone dominant emphysema, as defined by visual appearance on chest computed tomography scans, wasspecifically reported in the NETT (National Emphysema Treatment Trial) study, which demonstrated thatLVRS works best in this group of patients [16]. Further research using endobronchial valves as a less invasivemeans of LVRS initially targeted this group [17]. Post hoc analyses suggest that whether fissures are intact maybe more important than disease location or heterogeneity [61]. Patients with upper zone dominant emphysemaalso exhibit different genetic risk factors, implying variation in pathogenesis [62]. Bullous emphysema is alsotreated surgically, although patient selection and operative technique is much more individualised [63].

Overt or relative hypoxia occurs in COPD, especially in later stages. The basis for long-term oxygentherapy (LTOT; oxygen for >15 h per day) is derived from two landmark placebo-controlled randomisedcontrolled trials, the NOTT (Nocturnal Oxygen Therapy Trial) study [18] and the MRC (MedicalResearch Council) study [19], which demonstrated improved survival. The NOTT study also demonstrateda decrease in mean pulmonary artery pressure. LTOT is indicated for stable patients who have an arterialoxygen tension <7.3 kPa on two separate occasions or 7.3–8.0 kPa in the presence of pulmonaryhypertension, nocturnal hypoxia or secondary polycythaemia. LTOT is not restricted to type 1 respiratoryfailure; however, if used in type 2 patients, adverse effects on hypercapnia are generally excluded prior toprescription. Aside from LTOT, two other modes of oxygen therapy exist, ambulatory and short burst;both have been reviewed elsewhere [64]. Ambulatory oxygen is indicated in mobile patients who meetLTOT criteria and is commonly considered in others who exhibit exertional desaturation to <90%.Short-burst oxygen therapy criteria are poorly defined and no benefits have been reported [65].

Noninvasive ventilation (NIV) is used to treat type 2 respiratory failure and has a strong acute evidencebase in hospital [66] for COPD patients. The evidence concerning use of home NIV in COPD is

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contradictory and concerns have been raised about whether potential benefits on incidence of severeexacerbations and hospital admissions are appropriately balanced with poor HRQoL [20–23]. Morerecently, it has been shown to improve survival by 21% [24]; a systematic review is ongoing [67].

Eosinophilic COPD is a controversial area, mainly because of the issue of whether it is truly distinct fromasthma (overlap pathologies will be discussed later). Recent evidence suggests it may be identified by sputumcytokine profile [68]. Nevertheless, trials focussing on such patients have been published and suggest thatsteroids are more beneficial in this group than in other COPD patients [25]. Several studies have reportedthat use of sputum eosinophilia as a guide to the use of steroids was effective [26, 27, 69], and systemiceosinophil counts may also be a useful guide to treating exacerbations with oral corticosteroids [70]. Recentevidence suggests that blood eosinophil counts >2% predicted a response to ICS in several major COPDtrials [71], although these were post hoc analyses and further definitive work in this area is awaited.

Biomass fuel COPD is common in females, particularly in the developing world [72]. Airway predominantphenotypes appear to be more common, with bronchial hyperresponsiveness (BHR) being a particularfeature in wood smoke exposure [73]. Consistent with this is the reported increased prevalence of anoverlap between asthma and COPD [74]. Systemic and pulmonary inflammation is similar to cigarettesmoke-induced disease [75, 76], with less emphysema [77] and less rapid FEV1 decline [78]. Patientsdecline more slowly if the biomass exposure is reduced [28], but is not clear whether inhaled therapiesused for “usual COPD” are of similar efficacy. The presence of BHR and overlap with asthma suggests thatICS might be an effective strategy, though no clinical trials have been reported yet.

Subgroups with less clear implications for therapyPulmonary hypertension in COPD adversely affects survival and exercise capacity. Although oxygentherapy protects against progression of pulmonary hypertension in patients with advanced COPD, its useis limited to those meeting LTOT criteria. Vasoactive compounds used in primary pulmonaryhypertension (sildenafil, bosentan and nitric oxide) have been investigated in COPD [79–83]. Some trialsshowed worsening HRQoL in treated patients, hence they are not used routinely, although individualpatient trials are employed in selected patients by specialist centres [84].

Systemic inflammation appeared to mark a subgroup of patients in the ECLIPSE study. This subgroupcomprised 16% of the whole group and had increased mortality and exacerbation rates compared topatients without inflammation [85]. It remains unclear whether this group should be treated differently;future trials of therapies aimed at reducing exacerbations might target this group, or include them as apre-specified subgroup analysis.

Stable state airway bacterial colonisation occurs in 30–70% of COPD patients, and may relate to sputumcolour [86–88]. It is defined as a significant pathogenic bacterial load (usually >1 × 106 cfu·mL−1) presentin sputum when the patient is well. Airway bacterial colonisation is associated with increased pulmonaryinflammation [89] and increased frequency of exacerbations [90]; hence, it seems a logical subtype totarget. Differences between laboratories, local bacterial patterns and lack of consistency of culture resultsover time may impact significantly on our ability to use this as a phenotype that directs therapy.Moxifloxacin has been tested to limited clinical benefit (exacerbation rates did not fall, although changesin bacteriology were seen) [91], and a macrolide trial is ongoing [92].

There is growing recognition that bronchiectasis may occur in patients who have had COPD for some time,but its prevalence varies widely (30–70% of subjects), depending on the presence of AATD and the methodused to define bronchiectasis on computed tomography [93, 94]. Again it is unclear whether treatmentshould differ, even though there are implications for survival (COPD with bronchiectasis versus COPDwithout bronchiectasis, hazard ratio 2.54) [95] and recovery time from exacerbations [96]. Exacerbationfrequency has not been found to differ [95, 96], although colonisation is more common [96].

Airflow obstruction, aetiology of which is thought to be due to tuberculosis [97], is a poorly definedphenotype as it is not clear whether the underlying prognosis is the same as classical smoking-relatedCOPD or whether treatment should differ. It is likely that pathogenesis differs, but this has not beeninvestigated fully. Many clinicians will adopt treatment approaches outside the guidelines for “usualCOPD”, but it remains important to emphasise to non-specialists that not all fixed airflow obstruction is“usual COPD”. Early life events that impact on lung function [98] seem unlikely to be amenable totherapy later in life, but this too remains uncertain.

Constancy of COPD subgroupsIn general, COPD is regarded as a disease that is slowly progressive; thus, it should be relatively easy toselect a treatment at a given time-point that will remain useful for some time. However, there has beenlittle research into the progression of the subgroups we have proposed. It may be much harder to propose

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a specific therapy for those that vary unless very detailed monitoring is undertaken or the duration oftherapy is fixed.

There are a number of COPD subgroups that remain constant once present. The frequent exacerbatorsubgroup was relatively stable in the ECLIPSE study [51], as was systemic inflammation [85]. Whilsttherapies that target exacerbations may reduce their frequency [4], this positive treatment effect does notdetract from the fact that patients on a range of treatments in the ECLIPSE study still exhibited stableexacerbation frequency, enabling it to be considered a sufficiently stable feature to guide treatment.Chronic bronchitis is defined as sputum production on most days for at least 3 months within at least2 consecutive years [99], and consequently is probably constant enough to guide therapy. By definition,AATD is a constant phenotype as it is determined by genotype.

Other subgroups appear to develop over time but are sufficiently constant to guide therapy decisions overa few years. Upper zone dominant emphysema has not been studied longitudinally in usual COPD;however, in AATD, it is an early event prior to the development of lower zone dominant emphysemafollowed by homogenous disease [100]. This occurs over many years; thus, it is probably constant enoughto guide decision making on treatment such as chronic bronchitis. Longitudinal blood gas studies have notbeen commonly carried out in COPD, although type 2 failure does develop over time, occurring in 24% ofpatients who have had an acidotic hypercapnic exacerbation 5 years after the first event [101]. Predictorsof hypoxia and hypercapnia include lung function and body composition [102]. What data are availablesuggest that progression of blood gas changes occurs in COPD, but that changes are slow enough (outsideexacerbations) to enable gases to be used to guide therapy.

Phenotypes where variation occurs over time are also seen in COPD. Pulmonary hypertension usually occurslate in disease [103], although it can occur alongside mild COPD [104]. Probably the only relevant clinicalfeature to define constancy is whether it is ever reported to disappear once it has developed; intuitively onewould imagine that it is as constant as the degree of respiratory failure though this is not supported bypublished evidence. One small study has shown that pulmonary artery pressure varies with exacerbations andexercise [105]; animal studies also imply phases of remission [106]. There have been few published studiesdetailing longitudinal changes in sputum bacterial content in stable COPD. Data in AATD suggests that it doesnot always stay the same [107], Moraxella catarrhalis and Pseuodomonas aeruginosa are capable of spontaneousremission in COPD [108, 109], and serial cultures during clinical trials also demonstrate variability [10]. Itseems unlikely that colonisation can be defined on the basis of a single sputum culture when stable, but itmight become a sufficiently constant phenotype to guide therapy if the definition can be better clarified.

Clinically relevant subgroups in asthmaBronchial asthma is a complex disease with many underlying mechanisms and, therefore, can beconsidered a syndrome containing subgroups with important similarities but also differences caused byvariable underlying aetiologies [1]. Some subgroups described in the literature are based on clinicalfeatures found in asthma databases and cluster analyses; molecular and genetic approaches have also beenwidely used [110]. This merging of clinical and pathological features has been reviewed extensivelyelsewhere [111], using the term endotype to delineate this way of defining disease. Within this review, wehave chosen to focus on clinically relevant subgroups rather than endotypes, as this may be more useful inclinical practice, although discussion of some molecular elements is unavoidable.

Subgroups with treatment implicationsA number of distinct asthma phenotypes have treatment implications and are summarised in table 3.There is a degree of overlap in that aspirin-sensitive asthma (ASA), which is caused by increased cysteinylleukotriene production exacerbated by nonsteroidal anti-inflammatory drugs, is often accompanied bysevere eosinophilic rhinosinusitis and nasal polyps. Therefore, it has many features of atopic/allergicasthma, which is often eosinophilic, and is associated with elevated IgE, exhaled nitric oxide fraction(FeNO) and periostin levels [125]. Nonatopic, noneosinophilic asthma typically demonstrates lower airwayhyperresponsiveness [126, 127] and lower corticosteroid responsiveness [127].

Based on cluster analysis [128], age at disease onset is a key differentiating factor linked to underlyinggenetic/molecular features, although it does not influence treatment directly. Nevertheless, it is clear thatcertain asthma subgroups, which vary with age, will require different treatment. Early-onset asthma isoften more atopic/allergic, and ORMDL3 polymorphisms exhibit a stronger association with childhoodand severe asthma [129, 130]. These observations suggest that there are different disease mechanisms inyounger patients, which have been partly proven by studies of airway cells. Four inflammatory subgroupsare distinguishable in induced sputum: eosinophilic, neutrophilic, paucigranulocytic and mixedgranulocytic [131]. For the purposes of treatment, this tends to be divided into eosinophilic andnoneosinophilic disease. Supporting this simplified sub-division, molecular phenotyping showed a

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T-helper (Th)2-high gene signature in airway epithelial tissue in 50% of mild asthmatics, and wasassociated with more atopy and response to ICS therapy [132]. The remaining patients showed a Th2-lowgene signature similar to healthy controls, with less airway obstruction, lower hyperreactivity and lowerresponse to ICS. This implies that selection could be applied to the use of ICS and, in particular,high-dose ICS, based on airway eosinophilia. Trials using this strategy have had some success [115], and itis supported by the latest severe asthma guidelines [114]. Newer drugs targeting severe eosinophilic asthmaare also emerging; most are monoclonal antibodies that are likely to be used in highly selected populations.Examples include mepolizumab (anti-interleukin (IL)-5) [115], and lebrikizumab (anti-IL-13), the latterbeing useful in patients with elevated periostin [113]. However, the relationship between eosinophilia andother features of asthma, such as airway hyperresponsiveness, is by no means clear cut; indeed, they maybe inherited separately [133], hence this cannot be the only way in which we define our phenotypes anddesign new treatments. Noneosinophilic disease has shown some response to macrolide therapy [116, 117],although this is not a widely recommended treatment strategy [114].

Other clinical features can be used to identify patients who fall into subgroups that may influencemanagement. For instance, early-onset allergic, exercise-induced asthma (EIA) and ASA phenotypesbelong to the Th2-high form of disease while neutrophilic asthma and smooth-muscle mediatedpaucigranulocytic asthma belong to the non-Th2 group [110]. Sputum cell counts may be impractical forroutine phenotyping, particularly in primary care; hence, a detailed history (age of onset, atopy, aspirinsensitivity, smoking, etc.) is key to identifying subgroups and tailoring treatment in clinical practice. Inallergic asthma, avoidance of triggers may be a strategy, although the utility of avoidance for house dustmite allergy is debatable [134]. Omalizumab is a well-validated strategy for allergic asthma with high IgE,which reduces corticosteroid use and exacerbation rates [135] and improves long-term control [136].Patients with ASA should avoid aspirin and nonsteroidal anti-inflammatory drugs. Although there is someevidence that leukotriene inhibition is particularly effective in ASA, it is not consistent [123, 137] andstandard asthma management should be followed.

History also identifies occupational asthma, which is best diagnosed by the occupational asthma systemscore on serial peak expiratory flow rate testing or specific provocation challenge [138]. It is subdividedinto asthma precipitated by the exposure or pre-existing asthma that is worsened by exposure. Sputumeosinophil counts and FeNO relate reasonably well to specific provocation challenge [139], althoughdistinct groups without FeNO elevation are identifiable [140]. Cessation or reduction of exposure is key, asdelineated in a systematic review by a European Respiratory Society Task Force [124]. Patients withcontinued exposure tend to progress faster in terms of lung function decline and symptoms [141].

Fungal sensitisation in asthma is common with an estimated prevalence of up to 30% [142], covering aspectrum from allergic bronchopulmonary aspergillosis (ABPA) through severe asthma with fungalsensitisation (SAFS) and asymptomatic sensitisation. Diagnosis is made by examining serum IgE, and byperforming specific radioallergosorbent tests to Aspergillus and Aspergillus precipitins. Both ABPA andSAFS respond to antifungals [118, 119], although their efficacy is debatable [114]. Susceptibility to fungalinfection and sensitisation may be genetically determined (e.g. human leukocyte antigen type [143] andToll-like receptors [144]).

TABLE 3 Asthma subgroups and their stability over time

Subgroup Treatment [Ref.]

Atopic/allergic Avoidance of triggers, ICS, CS, anti-IgE, anti-IL-5, anti-IL-13 [112–114]Eosinophilic Avoidance of triggers, ICS, CS, anti-IgE, anti-IL-5, anti-IL-13 [115]Non-eosinophilic Macrolides, less likely to respond well to ICS [116, 117]ABPA and SAFS Antifungals [118, 119]Churg–Strauss syndrome Steroids, cyclophosphamide, rituximab [120, 121]Exercise-induced asthma ICS [122]Aspirin sensitive Avoidance of aspirin, leukotriene inhibition [123]Occupational Avoidance of occupational agent [124]

Aspirin sensitive and occupational subgroups appear to stay the same over time; other subgroups may varyaccording to treatment or the clinical picture is unclear. In each subgroup, some of the treatment optionsand relevant references are shown (see text for further details). All have shown either symptomaticimprovement, reduction in exacerbations or both. Bronchodilator agents are not listed and should be usedin all subgroups when required or other therapies with equal efficacy should be used. ABPA: allergicbronchopulmonary aspergillosis; SAFS: severe asthma with fungal sensitisation; ICS: inhaledcorticosteroids; CS: corticosteroid; IL: interleukin.

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Churg–Strauss syndrome is a rare, progressive, systemic disorder characterised by eosinophilia,extravascular necrotising granulomas, worsening asthma, lung infiltrates and eventually antineutrophilcytoplasmic antibody-positive systemic vasculitis [145]. Significant heterogeneity is seen at presentationand longer term. Lower baseline eosinophil counts predict mortality [146]. Precise management differsaccording to disease severity (e.g presence of glomerulonephritis), but in general involves aggressiveimmunosuppression, often with cylophosphamide alongside corticosteroids [120]. Rituximab has also beenused with some success [121].

EIA is an acute transient airway narrowing that occurs during and, most often, after exercise. EIA isdefined as a decrease in FEV1 >10% from baseline measured up 30 min after exercise. A higher prevalenceof EIA has been reported among elite athletes, especially in endurance sports, such as rowing andcross-country skiing, compared to the general population [147]. However, some elite athletes with EIAhave neither a history of childhood asthma nor a family history of asthma, suggesting that environmentalfactors are more important than genetic inheritance [148]. The most effective therapy for EIA is regularuse of ICS [122]. Early use of leukotriene inhibition may be equally effective [149, 150].

Subgroups with less clear implications for therapySevere refractory asthma is an area of intense research, which many newer therapies are being targetedtowards. However, this is also heterogeneous with eosinophilic and noneosinophilic phenotypes [151],implying that severity may not be the feature that drives specific treatment. Nevertheless, at least part ofsevere asthma has a different pathobiology compared to nonsevere disease. For example, innate immunityin the airway is influenced by glucocorticoids [152] and there have been recent insights into the role thatinnate immunity plays in steroid refractory severe disease [153].

Neutrophilic asthma also exhibits some innate immune features [154], although whether this is a truephenotype remains debatable. Neutrophilic asthma is associated with low FEV1, air trapping [155] andsmoking [156], and thus may represent overlap with COPD, or indeed with other pro-inflammatorytrigger factors. For instance, two studies have reported clusters of older, obese, female, nonatopicasthmatics [128, 157]. “Extensive remodelling asthma” is characterised by pronounced airway remodellingand minimal inflammation [158], increased airway smooth muscle mass may also occur. One cause maybe an intrinsic airway smooth muscle abnormality. Whether extensive remodelling has therapeuticimplications remains uncertain.

Reconciling variability and triggers with subgroup identificationUnlike COPD, asthma is classically thought to be variable. This brings problems when defining subgroups,as patients may change over time or in response to treatment. We suggest that identifying the currentsubgroup is the most important factor when modulating therapy. Knowing the subgroup at initialdiagnosis may also help but past features should not preclude altering treatment based on currentpresentation.

TriggersSpecific trigger or detrimental factors are interesting elements of phenotyping. Classical triggers (allergensand occupation) that change treatment are part of our subgroup definitions. Recognised triggers that donot alter specific asthma management include obesity, smoking, gastro-oesophageal reflux disease(GORD), menstrual cycle and air pollution. Obesity is a risk factor for asthma, and asthma often causesweight gain; there is no consensus about the exact relationship between the two. One cluster analysisidentified a noneosinophilic obese group of patients [128], another has reported a nonatopic obese groupwho required multiple courses of corticosteroids [157]. However, a recent meta-analysis reported that bodymass index (BMI) was a key feature of asthma subgroups but, of the clusters that were predominantlyobese, clinical and inflammatory differences occurred between them suggesting heterogeneity independentof obesity [159]. Weight loss appears to help asthma control [160]; however, since weight loss haspluripotent health benefits, we felt it did not represent specific asthma management. Smoking alsoinfluences the course of asthma. Asthmatics who smoke show poor response to corticosteroid therapy,more frequent exacerbations and worse lung function progressing to fixed obstruction, but smoking mightmake airways disease worse.

An association between asthma and GORD has been the subject of considerable investigation. There is nodoubt that GORD is more common in asthma [161] and this has led to the suggestion that refluxtreatment may improve asthma control. Several large clinical trials [162, 163] and a Cochrane review [164]have been published, demonstrating that treatment with high-dose proton-pump inhibitor improves coughbut has no effect on asthma symptoms, lung function or exacerbation rates.

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17% of asthmatic females report worsening of symptoms near menses, and this perimenstrual asthmaphenotype is associated with higher BMI, lower forced vital capacity, GORD, aspirin sensitivity and poorasthma control [165]. However, healthy females exhibit similar changes in pulmonary physiology acrosstheir menstrual cycle to those with asthma [166], and multivariate analysis has shown that baseline asthmacharacteristics can differ in those who report symptom changes across their cycle [167]. As such, it is likelythat sex hormones represent a trigger, and that perimenstrual asthma is not a truly different subtype.

Constancy of asthma subgroupsThe constancy of asthma phenotypes over time, or after therapy implementation, is not as clear in COPD.Asthma is variable, thus phenotypes ought to change over time, but few published data exist. Those thatappear to remain constant are occupational asthma and ASA. Occupational asthma progresses faster ifexposure continues [124], implying that the underlying disease process is unchanged. The risk ofprecipitating severe exacerbations means that testing whether patients remain aspirin sensitive long-termhas rarely been performed. Case reports demonstrate that aspirin sensitivity can develop in patients whohave previously taken it without respiratory problems [168], but studies which have challenged known ASApatients have shown that most remain sensitive [169, 170]. Asthma subgroups that clearly change withtreatment include ABPA, SAFS and Churg–Strauss syndrome. Atopy and allergy may also remit, usuallyover time but occasionally with treatment, such as desensitisation [171]. For example, 21% of children aged<2 years with severe peanut allergy will be tolerant by 5 years of age [172]. Remission of asthma was equallycommon in allergic/atopic and nonatopic patients in a large prospective cohort study of childhood-onsetasthma, averaging 65% of patients [173]. Even in adults, allergic responses vary over time, as demonstratedby the fact that 39% of patients have different results on serial skin-prick testing (mostly gaining newallergies), but in 13% of cases allergies were lost and in 4% allergies were gained and lost [174].

Published evidence is inconsistent regarding the constancy of asthmatic airway inflammation. In adults,50% of mild-to-moderate asthmatics have persistently noneosinophilic (often neutrophilic) disease and theremainder have persistent or intermittent eosinophilia [175]. Intermittent and persistent groups exhibitedsimilar clinical characteristics, and hence may represent a milder form of the same population.Therapeutically, the neutrophilic patients respond poorly to usual asthma therapy. Conversely, the sputuminflammatory phenotype proved inconsistent in asthmatic children [176]. This may also change withtreatment; for example, corticosteroids inhibit neutrophil apoptosis [177] such that neutrophilic asthmacould actually represent over-treated eosinophilic asthma. This hypothesis is supported by the observationthat corticosteroid withdrawal abolished neutrophilic subjects among moderate asthmatics [156].

Subgroups shared between COPD and asthmaWhen a patient presents with symptoms of increased variability of airflow alongside partially reversibleairflow obstruction, it is known as the asthma–COPD overlap syndrome (ACOS) [178]. A consensusconference has proposed that an ACOS patient must fulfil two major criteria or one major and two minorcriteria from the following. 1) Major criteria: positive bronchodilator response (>400 mL and >15% FEV1),sputum eosinophilia or previous diagnosis of asthma. 2) Minor criteria: increased total serum IgE, historyof atopy or positive bronchodilator test (>200 mL and >12% FEV1) on at least two occasions [179]. ACOStypically includes patients with early-onset asthma and a long disease duration who then fulfil criteria forCOPD with age, COPD patients with increased reversibility and smoking asthmatics who have fixedairflow obstruction. Overall, 13–19% of patients with obstructive lung diseases have some overlap and thisincreases with age [180, 181]. In the UPLIFT (Understanding Potential Long-term Impacts of Tiotropium)trial, two-thirds of moderate-to-severe COPD patients exhibited bronchodilator responsiveness [182];however, most clinical trials for either asthma or COPD exclude patients with features of the other disease,implying that their results will be poorly generalisable in real-life. ACOS has been extensively reviewedelsewhere [178, 179]. Our reasoning for including it here is to revisit the concept in light of the morecomplex subgroups of both asthma and COPD that we have described. Its importance is that patientsexhibiting features consistent with ACOS are more likely to be frequent exacerbators [183], have morerespiratory symptoms, higher mortality [183], higher comorbidity rates [184], greater healthcare utilisation[184] and worse HRQoL [181].

Overlap patients are generally thought to exhibit phenotypes part way between COPD and asthma. For example,GIBSON and SIMPSON [178] reported prevalence of atopy that was highest in asthma (100%) intermediate inACOS (64%) and lowest in COPD (25%). There are some differences that may depend on the predominantpathology. Positive bronchodilator response observed in COPD is associated with increased eosinophilicinflammation [185] whilst irreversible COPD more frequently exhibits neutrophilia. Smoking asthmaticstypically have inflammatory features that resemble COPD with increased neutrophilia and sometimesairway remodelling [186]. Classical asthma drivers, such as occupation, are associated with fixed airflowobstruction after chronic exposure [187] and ABPA has also been reported in patients with COPD [188].

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During exacerbations of ACOS, airway mucosal eosinophils increase more than neutrophils [189] explaining theimprovement with systemic corticosteroids or ICS. Conversely, analysis of volatile organic compounds in severepersistent asthma compared to severe COPD showed that volatile organic compound patterns remaineddifferent, suggesting singular pathophysiological mechanisms [190]. Taken together, the evidence suggests thatthere may be aspects of shared pathogenesis that move treatment decisions to that of the subgroup irrespectiveof the primary diagnosis. Shared subgroups are shown in figure 2.

Examples of subgroups common to asthma and COPDThe evidence for treating overlap is far less extensive than for single pathology. In addition, it would bebeyond the scope of this article to review all shared subgroups comprehensively; thus, we have chosen afew pertinent examples. One significant shared phenotype where evidence exists for management iseosinophilic airways disease. The evidence that asthmatics with eosinophilia respond to steroids isincontrovertible, and a study from Leicester, UK, has demonstrated that patients with COPD and relativelyhigh blood eosinophils (>2%) respond better to oral steroids in the context of an exacerbation than thosewith lower levels [70]. Similar results have been reported for use of ICS [25–27, 69].

Frequent exacerbations in asthma can be associated with risk factors such as severe nasal sinus disease,GORD, recurrent respiratory infections and obstructive sleep apnoea [191]. Many, such as GORD, aresimilar to the risk factors for frequent exacerbation in COPD patients in the ECLIPSE study [51]. Similarstrategies to manage risk factors are advocated in both diseases, alongside potential additional therapiessuch as macrolides [10, 116, 192].

Messages for clinical practiceCharacterising patients with chronic respiratory symptoms may be more important than giving a label ofasthma or COPD in predicting prognosis and response to treatment. A lot of phenotypes have beendefined in the literature but some of them do not yet have treatment or prognostic implications. Asthmasubgroups, unlike COPD, are likely to change over time and the current phenotype should be regarded asthe most important factor to guide treatment.

AcknowledgementsWe would like to thank GSK for organising the European Respiratory Network of Excellence event that stimulated thedebates leading to this review.

Overlap phenotype

Churg–Strauss

Type 1 respiratory

failure

Type 2 respiratory

failure

Upper zone

emphysema

Exercise induced

Aspirin sensitive

COPDAsthmaABPA

Frequent exacerbator

Extrinsic asthma

Long disease duration

Smoking asthma

Non-eosinophilic inflammation

Eosinophilic inflammation

Reversibility to β2-agonists

COPD with high IgE

Occupational, chronic exposure

Chronic bronchitis

α1-antitrypsin deficiency

FIGURE 2 Schematic diagram of the shared subgroups between asthma and chronic obstructive pulmonary disease(COPD). The figure shows phenotypes that are recognised in both conditions. The placement/colour of the shapesindicates the degree to which they are recognised in asthma and COPD. ABPA: allergic bronchopulmonary aspergillosis.

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